Non-human animals comprising a modified cacng1 locus

Abstract

Non-human animal cells and non-human animals comprising a humanized Cacng1 locus and methods of using such non-human animal cells and non-human animals are provided. Non-human animal cells or non-human animals comprising a humanized Cacng1 locus express a human CACNG1 protein or fragments thereof.

We claim: 
     
         1 . A non-human animal cell, wherein the non-human animal cell comprises a nucleic acid sequence encoding a heterologous Calcium Voltage-Gated Channel Auxiliary Subunit Gamma 1 (CACNG1) protein or a portion thereof. 
     
     
         2 . The non-human animal cell of  claim 1 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof comprises:
 (i) a nucleic acid sequence comprising exon 1 of a human CACNG1 gene or a portion thereof;   (ii) a nucleic acid sequence comprising exon 2 of a human CACNG1 gene or a portion thereof;   (iii) a nucleic acid sequence comprising exon 3 of a human CACNG1 gene or a portion thereof;   (iv) a nucleic acid sequence comprising exon 4 of a human CACNG1 gene or a portion thereof; or   (v) any combination of (i)-(iv).   
     
     
         3 . The non-human animal cell of  claim 1 or claim 2 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof comprises:
 (i) a nucleic acid sequence comprising exon 1 of a human CACNG1 gene or a portion thereof;   (ii) a nucleic acid sequence comprising intron 1 of a human CACNG1 gene or a portion thereof;   (iii) a nucleic acid sequence comprising exon 2 of a human CACNG1 gene or a portion thereof;   (iv) a nucleic acid sequence comprising intron 2 of a human CACNG1 gene or a portion thereof;   (v) a nucleic acid sequence comprising exon 3 of a human CACNG1 gene or a portion thereof;   (vi) a nucleic acid sequence comprising intron 3 of a human CACNG1 gene or a portion thereof;   (vii) a nucleic acid sequence comprising exon 4 of a human CACNG1 gene or a portion thereof;   (viii) a nucleic acid sequence comprising a 3′ untranslated region (UTR) of a human CACNG1 gene; or   (ix) any combination of (i)-(viii).   
     
     
         4 . The non-human animal cell of any one of  claims 1-3 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof comprises, consists essentially of, or consists of a nucleic acid sequence selected from the group consising of a nucleic acid sequence set forth as SEQ ID NO:5, a nucleic acid sequence set forth as SEQ ID NO:27, and a nucleic acid sequence set forth as SEQ ID NO:28. 
     
     
         5 . The non-human animal cell of any one of  claims 1-4 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or portion thereof is at an endogenous Cacng1 locus. 
     
     
         6 . The non-human animal cell of any one of  claims 1-5 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or portion thereof replaces an orthologous endogenous nucleic acid sequence encoding an endogenous CACNG1 protein or a portion thereof. 
     
     
         7 . The non-human animal cell of any one of  claims 1-6 , wherein the non-human animal cell, comprises an endogenous Cacng1 locus, and wherein the endogenous Cacng1 locus comprises a heterozygous or homozygous replacement of an endogenous nucleic acid sequence encoding an endogenous CACNG1 protein or a portion thereof with the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof,
 wherein the endogenous nucleic acid sequence encoding the endogenous CACNG1 protein or the portion thereof and the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof are orthologous.   
     
     
         8 . The non-human animal cell of any one of claims  1 - 8 , wherein the heterologous CACNG1 protein or the portion thereof comprises an amino acid sequence of a human CACNG1 protein or a portion thereof. 
     
     
         9 . The non-human animal cell of any one of  claims 1-8 , wherein the heterologous CACNG1 protein or the portion thereof comprises
 (i) an amino acid sequence set forth as SEQ ID NO:8;   (ii) an amino acid sequence set forth as SEQ ID NO: 10;   (iii) an amino acid sequence set forth as SEQ ID NO: 12;   (iv) an amino acid sequence set forth as SEQ ID NO: 14;   (v) an amino acid sequence set forth as SEQ ID NO: 16;   (vi) an amino acid sequence set forth as SEQ ID NO:18;   (vii) an amino acid sequence set forth as SEQ ID NO:20;   (viii) an amino acid sequence set forth as SEQ ID NO:22;   (ix) an amino acid sequence set forth as SEQ ID NO:24; or   (x) any combination of (i)-(ix).   
     
     
         10 . The non-human animal cell of any one of  claims 1-3 or 5-9 , wherein the heterologous CACNG1 protein or the portion thereof comprises an amino acid sequence set forth as SEQ ID NO: 4. 
     
     
         11 . The non-human animal cell of any one of  claims 1-10 , wherein the non-human animal cell is a mammalian cell. 
     
     
         12 . The non-human animal cell of any one of  claims 1-11 , wherein the mammalian cell is a rodent cell. 
     
     
         13 . The non-human animal cell of any one of  claims 1-12 , wherein the rodent cell is a rat cell or a mouse cell. 
     
     
         14 . The non-human animal cell of any one of  claims 1-13 , wherein the heterologous CACNG1 protein is a full-length human CACNG1 protein, and wherein the non-human animal cell expresses, on its cell surface, the full-length human CACNG1 protein. 
     
     
         15 . The non-human animal cell of any one of  claims 1-14 , wherein the non-human animal cell is a non-human animal skeletal muscle cell that expresses, on its cell surface, the heterologous CACNG1 protein or portion thereof. 
     
     
         16 . The non-human animal cell of any one of  claims 1-13 , wherein the non-human animal cell is a non-human animal cell that does not express, on its cell surface, the heterologous CACNG1 protein or portion thereof. 
     
     
         17 . The non-human animal cell of any one of  claims 1-13 and 16 , wherein the non-human animal cell does not express, on its cell surface, the heterologous CACNG1 protein or the portion thereof, and wherein the non-human animal cell is not a skeletal cell. 
     
     
         18 . The non-human animal cell of any one of  claims 1-13 and 16-17 , wherein the non-human animal cell does not express, on its cell surface, the heterologous CACNG1 protein or portion thereof, and wherein the non-human animal cell is a pluripotent cell. 
     
     
         19 . The non-human animal cell of any one of  claims 1-13 and 16-18 , wherein the non-human animal cell does not express, on its cell surface, the heterologous CACNG1 protein or portion thereof, and wherein the non-human animal cell is an embryonic stem cell. 
     
     
         20 . The non-human animal cell of any one of  claims 1-13 and 16-18 , wherein the non-human animal cell does not express, on its cell surface, the heterologous CACNG1 protein or portion thereof, and wherein the non-human animal cell is a germ cell. 
     
     
         21 . The non-human animal cell of any one of claims  1 - 21 , wherein the non-human animal cell is a mouse cell. 
     
     
         22 . The non-human animal cell of any one of  claims 1-21 , wherein the non-human animal cell is a mouse cell and wherein the nucleic acid sequence encoding a heterologous CACNG1 protein or portion thereof comprises, consists essentially of, or consists of a nucleic acid sequence set forth as SEQ ID NO: 6. 
     
     
         23 . A non-human animal comprising a nucleic acid sequence encoding a heterologous Calcium Voltage-Gated Channel Auxiliary Subunit Gamma 1 (CACNG1) protein or a portion thereof. 
     
     
         24 . The non-human animal of  claim 23 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof comprises:
 (i) a nucleic acid sequence comprising exon 1 of a human CACNG1 gene or a portion thereof;   (ii) a nucleic acid sequence comprising exon 2 of a human CACNG1 gene or a portion thereof;   (iii) a nucleic acid sequence comprising exon 3 of a human CACNG1 gene or a portion thereof;   (iv) a nucleic acid sequence comprising exon 4 of a human CACNG1 gene or a portion thereof; or   (v) any combination of (i)-(iv).   
     
     
         25 . The non-human animal of  claim 23 or claim 24 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof comprises:
 (i) a nucleic acid sequence comprising exon 1 of a human CACNG1 gene or a portion thereof;   (ii) a nucleic acid sequence comprising intron 1 of a human CACNG1 gene or a portion thereof;   (iii) a nucleic acid sequence comprising exon 2 of a human CACNG1 gene or a portion thereof;   (iv) a nucleic acid sequence comprising intron 2 of a human CACNG1 gene or a portion thereof;   (v) a nucleic acid sequence comprising exon 3 of a human CACNG1 gene or a portion thereof;   (vi) a nucleic acid sequence comprising intron 3 of a human CACNG1 gene or a portion thereof;   (vii) a nucleic acid sequence comprising exon 4 of a human CACNG1 gene or a portion thereof;   (viii) a nucleic acid sequence comprising a 3′ untranslated region (UTR) of a human CACNG1 gene; or   (ix) any combination of (i)-(viii).   
     
     
         26 . The non-human animal of any one of  claims 23-25 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof comprises, consists essentially of, or consists of a nucleic acid sequence selected from the group consising of a nucleic acid sequence set forth as SEQ ID NO:5, a nucleic acid sequence set forth as SEQ ID NO:27, and a nucleic acid sequence set forth as SEQ ID NO:28. 
     
     
         27 . The non-human animal of any one of  claims 23-26 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or portion thereof is at an endogenous Cacng1 locus. 
     
     
         28 . The non-human animal of any one of  claims 23-27 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or portion thereof replaces an orthologous endogenous nucleic acid sequence encoding an endogenous CACNG1 protein or a portion thereof. 
     
     
         29 . The non-human animal of any one of  claims 23-28 , wherein the non-human animal, comprises an endogenous Cacng1 locus, and wherein the endogenous Cacng1 locus comprises a heterozygous or homozygous replacement of an endogenous nucleic acid sequence encoding an endogenous CACNG1 protein or a portion thereof with the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof,
 wherein the endogenous nucleic acid sequence encoding the endogenous CACNG1 protein or the portion thereof and the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof are orthologous.   
     
     
         30 . The non-human animal of any one of  claims 23-29 , wherein the heterologous CACNG1 protein or the portion thereof comprises an amino acid sequence of a human CACNG1 protein or a portion thereof. 
     
     
         31 . The non-human animal of any one of  claims 23-30 , wherein the heterologous CACNG1 protein or the portion thereof comprises
 (i) an amino acid sequence set forth as SEQ ID NO:8;   (ii) an amino acid sequence set forth as SEQ ID NO: 10;   (iii) an amino acid sequence set forth as SEQ ID NO: 12;   (iv) an amino acid sequence set forth as SEQ ID NO: 14;   (v) an amino acid sequence set forth as SEQ ID NO: 16;   (vi) an amino acid sequence set forth as SEQ ID NO:18;   (vii) an amino acid sequence set forth as SEQ ID NO:20;   (viii) an amino acid sequence set forth as SEQ ID NO:22;   (ix) an amino acid sequence set forth as SEQ ID NO:24; or   (x) any combination of (i)-(ix).   
     
     
         32 . The non-human animal of any one of  claims 23-31 , wherein the heterologous CACNG1 protein or the portion thereof comprises an amino acid sequence set forth as SEQ ID NO: 4. 
     
     
         33 . The non-human animal of any one of  claims 23-32 , wherein the non-human animal is a mammal. 
     
     
         34 . The non-human animal of any one of  claims 23-33 , wherein the mammal is a rodent. 
     
     
         35 . The non-human animal of any one of  claims 23-34 , wherein the rodent is rat or a mouse. 
     
     
         36 . The non-human animal of any one of  claims 23-35 , wherein the non-human animal comprises a non-human muscle cell that expresses, on its cell surface, a full-length human CACNG1 protein. 
     
     
         37 . The non-human animal of any one of  claims 23-36 , wherein the non-human animal comprises a non-human animal skeletal muscle cell that expresses, on its cell surface, the heterologous CACNG1 protein or portion thereof. 
     
     
         38 . The non-human animal of any one of  claims 23-37 , wherein the heterologous CACNG1 protein comprises a full-length human CACNG1 protein, and
 wherein the non-human animal comprises a non-human animal skeletal muscle cell that expresses, on a cell surface, the full-length human CACNG1 protein.   
     
     
         39 . The non-human animal of any one of  claims 23-38 , wherein the non-human animal comprises a non-human animal cell that does not express, on a cell surface, the heterologous CACNG1 protein or portion thereof. 
     
     
         40 . The non-human animal of any one of  claims 23-35 and 39 , wherein the non-human animal comprises a non-human animal germ cell that does not express, on a cell surface of its skeletal cells, the heterologous CACNG1 protein or the portion thereof. 
     
     
         41 . The non-human animal of any one of  claims 23-40 , wherein the non-human animal is a rat or a mouse. 
     
     
         42 . A non-human animal genome, wherein the non-human animal genome comprises a nucleic acid sequence encoding a heterologous Calcium Voltage-Gated Channel Auxiliary Subunit Gamma 1 (CACNG1) protein or a portion thereof. 
     
     
         43 . The non-human animal genome of  claim 42 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof comprises:
 (i) a nucleic acid sequence comprising exon 1 of a human CACNG1 gene or a portion thereof;   (ii) a nucleic acid sequence comprising exon 2 of a human CACNG1 gene or a portion thereof;   (iii) a nucleic acid sequence comprising exon 3 of a human CACNG1 gene or a portion thereof;   (iv) a nucleic acid sequence comprising exon 4 of a human CACNG1 gene or a portion thereof; or   (v) any combination of (i)-(iv).   
     
     
         44 . The non-human animal genome of  claim 42 or claim 43 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof comprises:
 (i) a nucleic acid sequence comprising exon 1 of a human CACNG1 gene or a portion thereof;   (ii) a nucleic acid sequence comprising intron 1 of a human CACNG1 gene or a portion thereof;   (iii) a nucleic acid sequence comprising exon 2 of a human CACNG1 gene or a portion thereof;   (iv) a nucleic acid sequence comprising intron 2 of a human CACNG1 gene or a portion thereof;   (v) a nucleic acid sequence comprising exon 3 of a human CACNG1 gene or a portion thereof;   (vi) a nucleic acid sequence comprising intron 3 of a human CACNG1 gene or a portion thereof;   (vii) a nucleic acid sequence comprising exon 4 of a human CACNG1 gene or a portion thereof;   (viii) a nucleic acid sequence comprising a 3′ untranslated region (UTR) of a human CACNG1 gene; or   (ix) any combination of (i)-(viii).   
     
     
         45 . The non-human animal genome of any one of  claims 42-44 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof comprises, consists essentially of, or consists of a nucleic acid sequence selected from the group consising of a nucleic acid sequence set forth as SEQ ID NO:5, a nucleic acid sequence set forth as SEQ ID NO:27, and a nucleic acid sequence set forth as SEQ ID NO:28. 
     
     
         46 . The non-human animal genome of any one of  claims 42-45 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or portion thereof is at an endogenous Cacng1 locus. 
     
     
         47 . The non-human animal genome of any one of  claims 42-46 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or portion thereof replaces an orthologous endogenous nucleic acid sequence encoding an endogenous CACNG1 protein or a portion thereof. 
     
     
         48 . The non-human animal genome of any one of  claims 42-47 , wherein the non-human animal genome comprises an endogenous Cacng1 locus, and wherein the endogenous Cacng1 locus comprises a heterozygous or homozygous replacement of an endogenous nucleic acid sequence encoding an endogenous CACNG1 protein or a portion thereof with the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof,
 wherein the endogenous nucleic acid sequence encoding the endogenous CACNG1 protein or the portion thereof and the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof are orthologous.   
     
     
         49 . The non-human animal genome of any one of  claims 42-48 , wherein the heterologous CACNG1 protein or the portion thereof comprises an amino acid sequence of a human CACNG1 protein or a portion thereof. 
     
     
         50 . The non-human animal genome of any one of  claims 42-49 , wherein the heterologous CACNG1 protein or the portion thereof comprises
 (i) an amino acid sequence set forth as SEQ ID NO:8;   (ii) an amino acid sequence set forth as SEQ ID NO: 10;   (iii) an amino acid sequence set forth as SEQ ID NO: 12;   (iv) an amino acid sequence set forth as SEQ ID NO: 14;   (v) an amino acid sequence set forth as SEQ ID NO:16;   (vi) an amino acid sequence set forth as SEQ ID NO:18;   (vii) an amino acid sequence set forth as SEQ ID NO:20;   (viii) an amino acid sequence set forth as SEQ ID NO:22;   (ix) an amino acid sequence set forth as SEQ ID NO:24; or   (x) any combination of (i)-(ix).   
     
     
         51 . The non-human animal genome of any one of  claims 42-50 , wherein the heterologous CACNG1 protein or the portion thereof comprises an amino acid sequence set forth as SEQ ID NO: 4. 
     
     
         52 . The non-human animal genome of any one of  claims 42-51 , wherein the non-human genome is a mammalian nucleic acid. 
     
     
         53 . The non-human animal genome of any one of  claims 42-52 , wherein the mammal is a rodent nucleic acid. 
     
     
         54 . The non-human animal genome of any one of  claims 42-53 , wherein the rodent is rat genome or a mouse nucleic acid. 
     
     
         55 . The non-human animal genome of any one of  claims 42-54  wherein the the non-human animal genome is a mouse nucleic acid. 
     
     
         56 . A chimeric nucleic acid molecule, comprising a nucleic acid sequence of a non-human animal Cacng1 gene that (a) encodes a CACNG1 protein and (b) is modified to comprise a replacement of a sequence encoding the CACNG1 protein or portion thereof with a homologous sequence encoding a heterologous CACNG1 protein or a portion thereof,
 wherein the chimeric nucleic acid molecule encodes a functional CACNG1 protein.   
     
     
         57 . The chimeric nucleic acid molecule of  claim 56 , wherein the chimeric nucleic acid sequence further comprises promoter and/or regulatory sequences of the non-human animal Cacng1 gene. 
     
     
         58 . The chimeric nucleic acid molecule of  claim 57 , wherein the homologous nucleic acid sequence comprises:
 (i) a nucleic acid sequence comprising exon 1 of a human CACNG1 gene or a portion thereof;   (ii) a nucleic acid sequence of intron 1 of a human CACNG1 gene or a portion thereof;   (iii) a nucleic acid sequence comprising exon 2 of a human CACNG1 gene or a portion thereof;   (iv) a nucleic acid sequence of intron 2 of a human CACNG1 gene or a portion thereof;   (v) a nucleic acid sequence comprising exon 3 of a human CACNG1 gene or a portion thereof;   (vi) a nucleic acid sequence of intron 3 of a human CACNG1 gene or a portion thereof;   (vii) a nucleic acid sequence comprising exon 4 of a human CACNG1 gene or a portion thereof;   (viii) a nucleic acid sequence of a 3′ untranslated region (UTR) of a human CACNG1 gene; or   (ix) any combination of (i)-(viii).   
     
     
         59 . The chimeric nucleic acid molecule of  claim 57 or claim 58 , wherein the modified non-human animal Cacng1 gene further comprises a drug selection cassette. 
     
     
         60 . The chimeric nucleic acid molecule of any one of  claims 57-59 , further comprising:
 (i) a 5′ homology arm upstream of the modified non-human animal Cacng1 gene; and   (ii) a 3′ homology arm downstream of the modified non-human animal Cacng1 gene.   
     
     
         61 . The chimeric nucleic acid of  claim 60 , wherein the 5′ homology arm and 3′ homology arm undergo homologous recombination with a non-human animal Cacng1 locus of interest, and
 wherein following homologous recombination with the non-human animal Cacng1 locus of interest, the modified non-human animal Cacng1 gene replaces the non-human animal Cacng1 gene at the non-human animal Cacng1 locus of interest and is operably linked to an endogenous promoter that drives expression of the non-human animal Cacng1 gene at the non-human animal Cacng1 locus of interest. 
 
     
     
         62 . The chimeric nucleic acid of  claim 60 or claim 61 , wherein:
 (i) the 5′ homology arm comprises a nucleic acid sequence set forth as SEQ ID NO: 25; or   (ii) the 3′ homology arm comprises a nucleic acid sequence set forth as SEQ ID NO:26.   
     
     
         63 . The chimeric nucleic acid molecule of any one of  claims 57-62 , wherein the nucleic acid sequence of the chimeric nucleic acid comprises a nucleic acid sequence set forth as SEQ ID NO:6. 
     
     
         64 . A method of making the non-human animal cell of any one of  claims 1-22 , comprising inserting the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof into the genome of the non-human animal cell. 
     
     
         65 . The method of  claim 64 , wherein the non-human animal cell is a non-human animal embryonic stem (ES) cell, and
 wherein the inserting comprises inserting the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof into the genome of the non-human animal ES cell to form a modified non-human animal ES cell comprising the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof in the genome of the non-human animal ES cell.   
     
     
         66 . The method of  claim 64 or claim 65 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof is inserted into an endogenous Cacng1 locus. 
     
     
         67 . The method of any one of  claims 64-66 , wherein the step of inserting comprises replacing an endogenous nucleic sequence encoding an endogenous CACNG1 protein or portion thereof with the nucleic acid sequence encoding the heterologous CACNG1 protein or portion thereof,
 wherein the endogenous nucleic sequence encoding an endogenous CACNG1 protein or portion thereof and the nucleic acid sequence encoding the heterologous CACNG1 protein or portion thereof are orthologous.   
     
     
         68 . The method of any one of  claims 64-67 , wherein the nucleic acid sequence encoding a heterologous CACNG1 protein or portion thereof comprises:
 (i) a nucleic acid sequence comprising exon 1 of a human CACNG1 gene or a portion thereof;   (ii) a nucleic acid sequence comprising exon 2 of a human CACNG1 gene or a portion thereof;   (iii) a nucleic acid sequence comprising exon 3 of a human CACNG1 gene or a portion thereof;   (iv) a nucleic acid sequence comprising exon 4 of a human CACNG1 gene or a portion thereof; or   (v) any combination of (i)-(iv).   
     
     
         69 . The method of any one of  claims 64-68 , wherein the nucleic acid sequence encoding a heterologous CACNG1 protein or portion thereof comprises:
 (i) a nucleic acid sequence comprising exon 1 of a human CACNG1 gene or a portion thereof;   (ii) a nucleic acid sequence of intron 1 of a human CACNG1 gene or a portion thereof;   (iii) a nucleic acid sequence comprising exon 2 of a human CACNG1 gene or a portion thereof;   (iv) a nucleic acid sequence of intron 2 of a human CACNG1 gene or a portion thereof;   (v) a nucleic acid sequence comprising exon 3 of a human CACNG1 gene or a portion thereof;   (vi) a nucleic acid sequence of intron 3 of a human CACNG1 gene or a portion thereof;   (vii) a nucleic acid sequence comprising exon 4 of a human CACNG1 gene or a portion thereof;   (viii) a nucleic acid sequence of a 3′ untranslated region (UTR) of a human CACNG1 gene; or   (ix) any combination of (i)-(viii).   
     
     
         70 . The method of any one of  claims 64-69 , wherein the nucleic acid sequence encoding a heterologous CACNG1 protein or portion thereof comprises, consists essentially of, or consists of a nucleic acid sequence selected from the group consising of a nucleic acid sequence set forth as SEQ ID NO:5, a nucleic acid sequence set forth as SEQ ID NO:27, and a nucleic acid sequence set forth as SEQ ID NO:28. 
     
     
         71 . The method of any one of  claims 64-70 , wherein the heterologous CACNG1 protein or portion thereof comprises an amino acid sequence of a human CACNG1 protein or portion thereof. 
     
     
         72 . The method of any one of  claims 64-71 , wherein the heterologous CACNG1 protein or portion thereof comprises
 (i) an amino acid sequence set forth as SEQ ID NO:8;   (ii) an amino acid sequence set forth as SEQ ID NO:10;   (iii) an amino acid sequence set forth as SEQ ID NO:12;   (iv) an amino acid sequence set forth as SEQ ID NO:14;   (v) an amino acid sequence set forth as SEQ ID NO:16;   (vi) an amino acid sequence set forth as SEQ ID NO:18;   (vii) an amino acid sequence set forth as SEQ ID NO:20;   (viii) an amino acid sequence set forth as SEQ ID NO:22;   (ix) an amino acid sequence set forth as SEQ ID NO:24; or   (x) any combination of (i)-(ix).   
     
     
         73 . The method of any one of  claims 64-72 , wherein the heterologous CACNG1 protein comprises an amino acid sequence set forth as SEQ ID NO: 4. 
     
     
         74 . The method of any one of  claims 64-73 , wherein the non-human animal cell is a mammalian cell. 
     
     
         75 . The method of any one of  claims 64-74 , wherein the mammalian cell is a rodent cell. 
     
     
         76 . The method of any one of  claims 64-75 , the rodent cell is a mouse cell or a rat cell. 
     
     
         77 . The method of any one of  claims 64-76 , wherein the non-human animal cell is a mouse cell and wherein the nucleic acid sequence encoding a heterologous CACNG1 protein or portion thereof comprises, consists essentially of, or consists of a nucleic acid sequence set forth as SEQ ID NO: 6. 
     
     
         78 . The method of any one of  claims 64-77 , wherein inserting comprises contacting the genome of the non-human animal cell with the chimeric nucleic acid molecule of any one of  claims 55-63 . 
     
     
         79 . The method of any one of  claims 64-78 , wherein inserting comprises contacting the genome of the non-human animal cell with the chimeric nucleic acid molecule of any one of  claims 56-63 . 
     
     
         80 . A method of making the non-human animal of any one of  claims 23-41 , comprising inserting a nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof into the genome of a non-human animal embryonic stem (ES) cell to form a modified non-human animal ES cell comprising the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof in the genome of the non-human animal ES cell;
 introducing the non-human animal ES cells into host embryo cells in vitro; and   gestating, in a non-human surrogate mother animal, the host embryo cells comprising the modified non-human animal ES cell, and wherein, after the gestating, the non-human surrogate mother animal births a non-human animal progeny comprising a germ cell comprising the nucleic acid sequence encoding the heterologous CACNG1 protein or portion thereof.   
     
     
         81 . The method of  claim 80 , wherein the nucleic acid sequence encoding the heterologous CACNG1 protein or the portion thereof is inserted into an endogenous Cacng1 locus. 
     
     
         82 . The method of  claim 80 or claim 81 , wherein the step of inserting comprises replacing an endogenous nucleic sequence encoding an endogenous CACNG1 protein or portion thereof with the nucleic acid sequence encoding the heterologous CACNG1 protein or portion thereof,
 wherein the endogenous nucleic sequence encoding an endogenous CACNG1 protein or portion thereof and the nucleic acid sequence encoding the heterologous CACNG1 protein or portion thereof are orthologous.   
     
     
         83 . The method of any one of  claims 80-82 , wherein the nucleic acid sequence encoding a heterologous CACNG1 protein or portion thereof comprises:
 (i) a nucleic acid sequence comprising exon 1 of a human CACNG1 gene or a portion thereof;   (ii) a nucleic acid sequence comprising exon 2 of a human CACNG1 gene or a portion thereof;   (iii) a nucleic acid sequence comprising exon 3 of a human CACNG1 gene or a portion thereof;   (iv) a nucleic acid sequence comprising exon 4 of a human CACNG1 gene or a portion thereof; or   (v) any combination of (i)-(iv).   
     
     
         84 . The method of any one of  claims 80-83 , wherein the nucleic acid sequence encoding a heterologous CACNG1 protein or portion thereof comprises:
 (i) a nucleic acid sequence comprising exon 1 of a human CACNG1 gene or a portion thereof;   (ii) a nucleic acid sequence of intron 1 of a human CACNG1 gene or a portion thereof;   (iii) a nucleic acid sequence comprising exon 2 of a human CACNG1 gene or a portion thereof;   (iv) a nucleic acid sequence of intron 2 of a human CACNG1 gene or a portion thereof;   (v) a nucleic acid sequence comprising exon 3 of a human CACNG1 gene or a portion thereof;   (vi) a nucleic acid sequence of intron 3 of a human CACNG1 gene or a portion thereof;   (vii) a nucleic acid sequence comprising exon 4 of a human CACNG1 gene or a portion thereof;   (viii) a nucleic acid sequence of a 3′ untranslated region (UTR) of a human CACNG1 gene; or   (ix) any combination of (i)-(viii).   
     
     
         85 . The method of any one of  claims 80-84 , wherein the nucleic acid sequence encoding a heterologous CACNG1 protein or portion thereof comprises, consists essentially of, or consists of a nucleic acid sequence selected from the group consising of a nucleic acid sequence set forth as SEQ ID NO:5, a nucleic acid sequence set forth as SEQ ID NO:27, and a nucleic acid sequence set forth as SEQ ID NO:28. 
     
     
         86 . The method of any one of  claims 80-85 , wherein the heterologous CACNG1 protein or portion thereof comprises an amino acid sequence of a human CACNG1 protein or portion thereof. 
     
     
         87 . The method of any one of  claims 80-86 , wherein the heterologous CACNG1 protein or portion thereof comprises
 (i) an amino acid sequence set forth as SEQ ID NO:8;   (ii) an amino acid sequence set forth as SEQ ID NO:10;   (iii) an amino acid sequence set forth as SEQ ID NO:12;   (iv) an amino acid sequence set forth as SEQ ID NO:14;   (v) an amino acid sequence set forth as SEQ ID NO:16;   (vi) an amino acid sequence set forth as SEQ ID NO:18;   (vii) an amino acid sequence set forth as SEQ ID NO:20;   (viii) an amino acid sequence set forth as SEQ ID NO:22;   (ix) an amino acid sequence set forth as SEQ ID NO:24; or   (x) any combination of (i)-(ix).   
     
     
         88 . The method of any one of  claims 80-87 , wherein the heterologous CACNG1 protein comprises an amino acid sequence set forth as SEQ ID NO: 4. 
     
     
         89 . The method of any one of  claims 80-88 , wherein the non-human animal is a mammal. 
     
     
         90 . The method of any one of  claims 80-89 , wherein the mammal is a rodent. 
     
     
         91 . The method of any one of  claims 80-90 , the rodent cell is a mouse cell or a rat cell. 
     
     
         92 . The method of any one of  claims 80-91 , wherein the non-human animal is a mouse and wherein the nucleic acid sequence encoding a heterologous CACNG1 protein or portion thereof comprises, consists essentially of, or consists of a nucleic acid sequence set forth as SEQ ID NO: 6. 
     
     
         93 . The non-human animal of any one of  claims 23-40 , or the non-human animal made according to the method of any one of  claims 80-92 , comprising an antigen-binding protein that binds the heterologous CACNG1 protein, wherein the non-human animal expresses the heterologous CACNG1 protein or an extracellular domain thereof on a surface of a skeletal muscle cell. 
     
     
         94 . The non-human animal of  claim 93 , wherein the heterologous CACNG1 protein is a human CACNG1 protein. 
     
     
         95 . The non-human animal of  claim 93 or claim 94 , wherein the non-human animal is a mouse. 
     
     
         96 . A non-human animal, non-human animal cell, or non-human animal genome comprising a knockout mutation of an endogenous Cacng1 gene. 
     
     
         97 . The non-human animal, non-human animal cell, or non-human animal genome of  claim 96 , wherein the knockout mutation comprises a deletion of the Cacng1 gene or a portion thereof. 
     
     
         98 . The non-human animal, non-human animal cell, or non-human animal genome of  claim 96 or claim 97 , wherein the knockout mutation comprises a deletion of the entire coding sequence of the Cacng1 gene. 
     
     
         99 . The non-human animal, non-human animal cell, or non-human animal genome of claim any one of  claims 96-98 , wherein the non-human animal, non-human animal cell, or non-human animal genome does not express any CACNG1 protein. 
     
     
         100 . The non-human animal, non-human animal cell, or non-human animal genome of claim any one of  claims 96-99 , wherein the non-human animal, non-human animal cell, or non-human animal genome does not exhibit any gross mutant phenotype. 
     
     
         101 . The non-human animal, non-human animal cell, or non-human animal genome of anyone of  claims 96-100 , wherein the non-human animal, non-human animal cell, or non-human animal genome comprises an endogenous Cacng1 locus comprising the sequence set forth as SEQ ID NO:29. 
     
     
         102 . A method of making a CACNG1 knockout non-human animal comprising modifying an endogenous Cacng1 locus of the non-human animal to comprise a knockout mutation. 
     
     
         103 . A targeting vector comprising:
 (i) a 5′ homology arm; and   (ii) a 3′ homology arm,   wherein the 5′ homology arm and 3′ homology arm undergo homologous recombination with a non-human animal Cacng1 locus of interest, and   wherein following homologous recombination with the non-human animal Cacng1 locus of interest, the targeting vector inserts a knockout mutation in the non-human animal Cacng1 gene at the non-human animal Cacng1 locus of interest.   
     
     
         104 . A non-human animal, non-human animal cell, or non-human animal genome made according to any method described herein.